A method of synthesizing resmetirom

Abstract

The application provides a synthesis method of resmetirom. Compound 1 is used as a starting material, is reacted with hydrazine hydrate to obtain compound 2, is chlorinated to obtain 3,6-dichloro-4-isopropyl pyridazine compound 3, is hydrolyzed to obtain compound 4, is condensed with compound 5 to obtain a key compound 6 of resmetirom, is subjected to nitrosation, is condensed with a cyanoacetamide compound 7 to obtain an intermediate compound 8, and is subjected to ring closure to obtain the target product resmetirom 9. The method has mild reaction conditions and high conversion rate. The route not only greatly shortens the synthesis route, greatly improves the route efficiency, reduces the process cost, but also reduces the nitrosamine risk, is beneficial to improving the purity of the final product, and is suitable for scale-up production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry and relates to a method for synthesizing resmetiro, a drug used to treat non-alcoholic fatty liver disease. Background Technology

[0002] Nonalcoholic steatohepatitis (NASH) is the main cause of fatty liver disease. If left uncontrolled, it can worsen into cirrhosis and even liver cancer, seriously impacting health and threatening life. Resmetirom (MGL-3196), an investigational thyroid hormone receptor β (THR-β) agonist from the US biotechnology company Madrigal, is the first successful Phase III clinical trial drug for NASH, meeting both primary and key secondary endpoints in the treatment of NAFLD and NASH patients. It is expected to be available as early as the second half of 2023. If successful, this new drug is likely to receive accelerated approval from the FDA, and the market prospects for its raw materials and key intermediates are very promising.

[0003] Resimetiro's chemical name is 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-carboxynitrile. Existing synthetic strategies involve the key intermediate of resimetiro, 6-(4-amino-2,6-dichlorophenyl)-4-isopropylpyridazin-3(2H)-one, whose structural formula is as follows:

[0004]

[0005] PCT patent WO2014043706A reports a synthetic route for preparing resimetiro using the key intermediate 6-(4-amino-2,6-dichlorophenyl)-4-isopropylpyridazine-3(2H)-one. The route involves diazotization of the key intermediate aniline with sodium nitrite, followed by condensation with ethyl (2-cyanoacetamido) carbonate, and then cyclization with potassium acetate in dimethylacetamide at high temperature to obtain the target product. The route is as follows:

[0006]

[0007] The patent also reports two synthetic methods for the key intermediate 6-(4-amino-2,6-dichlorophenyl)-4-isopropylpyridazine-3(2H)-one. Method one uses 3,6-dichloropyridazine as the starting material, which is condensed with 4-amino-2,6-dichlorophenol. Then, a one-pot aminoacylation protection process is used to obtain an intermediate state, followed by chlorination. Next, isopropyl magnesium chloride is used to add to the double bond of this intermediate state. After bromination and a one-pot hydrolysis to remove hydrobromic acid, an aromatization reaction is completed. Finally, the amino protection is removed to obtain the key intermediate 6-(4-amino-2,6-dichlorophenyl)-4-isopropylpyridazine-3(2H)-one. The route is shown below:

[0008]

[0009] Method two, based on method one, utilizes magnesium isopropene bromide to add to the double bond, followed by aromatization via double bond migration using the strong base potassium hydroxide, and a one-pot removal of the amino protecting group to yield the key intermediate 6-(4-amino-2,6-dichlorophenyl)-4-isopropylpyridazine-3(2H)-one. The route is shown below:

[0010]

[0011] Currently, the synthesis of resmetiro uses the cyclization method of ethyl (2-cyanoacetamido) carbonate, which is expensive. Furthermore, the two methods for synthesizing the key intermediate 6-(4-amino-2,6-dichlorophenyl)-4-isopropylpyridazine-3(2H)-one require Grignard reagents for alkylation in key steps. However, since the substrates contain multiple active hydrogen atoms (NH), additional Grignard reagents are needed, further increasing costs. In addition, the numerous steps result in low overall yield and excessively high cost. Moreover, the synthesis of resmetiro uses sodium nitrite for diazotization, and the subsequent key cyclization reaction uses N,N-dimethylacetamide as a solvent under high-temperature heating, further increasing the risk of nitrosamine impurities in the final product. In summary, this route for the synthesis of resmetiro involves many steps, low overall yield, high cost, and a significant risk of nitrosamine impurities, leading to significant purification challenges. Therefore, a simpler, lower-cost method suitable for industrial production is still needed. Summary of the Invention

[0012] To address the shortcomings of existing technologies, the purpose of this invention is to provide a synthetic method for resimetiro that has a shorter synthetic route, simpler operation, higher yield, higher product purity, and is suitable for industrial production.

[0013] To achieve the purpose of the invention, this invention provides a novel intermediate compound 8 of resimetiro.

[0014] A resmetiro intermediate compound 8 has the following structural formula:

[0015]

[0016] This invention also provides a method for synthesizing the resimetidine intermediate compound 8, which adopts the following technical solution:

[0017] A method for synthesizing resmetrol intermediate compound 8 includes diazotizing compound 6 with a nitrosating agent and then condensing it with cyanoacetamide 7 to obtain intermediate compound 8;

[0018]

[0019] Preferably, in the condensation reaction, the diazotization reaction is carried out without acid or with acid selected from hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid; sodium nitrite, isoamyl nitrite, or tert-butyl nitrite is selected as the nitrosating agent; the additive is selected from sodium acetate, potassium acetate, or acetic acid; the reaction solvent is selected from dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, ethyl acetate, isopropyl acetate, methanol, ethanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, acetonitrile, or water; and the reaction temperature is -20 to 60°C.

[0020] The method for synthesizing resimetidine provided by this invention adopts the following technical solution:

[0021] A method for synthesizing resimetiro includes cyclizing compound 8 in the presence of a carbonylating agent to obtain the target product 9;

[0022]

[0023] Preferably, in the cyclization reaction, the carbonylating agent is selected from phosgene, methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, tert-butyl chloroformate, phenyl chloroformate, dimethyl carbonate, diethyl carbonate, tert-butylphenyl carbonate, carbonyl diimidazole, or Boc anhydride; the agent, with or without alkali, is selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, DMAP, pyridine, or DABCO; the reaction solvent is selected from dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, or acetonitrile; and the reaction temperature is -20 to 110°C.

[0024] This invention also provides a method for synthesizing 6, a key intermediate compound of resimeltiro, comprising the following steps:

[0025] (1) Compound 1 was cyclized by reacting it with hydrazine hydrate to obtain compound 2;

[0026]

[0027] (2) Compound 2 was chlorinated in the presence of a chlorinating agent to obtain compound 3;

[0028]

[0029] (3) Compound 3 was hydrolyzed with the aid of additives to obtain compound 4;

[0030]

[0031] (4) Compound 4 and compound 5 were condensed under the action of a base to obtain intermediate compound 6;

[0032]

[0033] Preferably, in step (1), the reaction solvent is selected from ethyl acetate, isopropyl acetate, methanol, ethanol, isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, or acetonitrile; no additives are selected, or the additives are selected from acetic acid, trifluoroacetic acid, or p-toluenesulfonic acid; and the reaction temperature is 0–110°C.

[0034] Preferably, in step (2), the chlorination reaction is carried out without or with alkali, and is selected from triethylamine, diisopropylethylamine, N,N-dimethylaniline, pyridine, DMAP, or DABCO; the chlorination reagent is selected from thionyl chloride, phosphorus trichloride, phosphine oxychloride, or phenyl dichlorophosphate; the reaction solvent is selected from dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, or acetonitrile; and the reaction temperature is -20 to 110°C.

[0035] Preferably, in the hydrolysis reaction of step (3), the additives are acetic acid, sodium acetate, lithium hydroxide, sodium hydroxide or potassium hydroxide; the reaction temperature is -20 to 110°C.

[0036] Preferably, in step (4), the condensation reaction involves adding an alkali selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, LiHMDS, n-butyllithium, triethylamine, diisopropylethylamine, N,N-dimethylaniline, pyridine, DMAP, or DABCO; the reaction solvent is selected from dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, or acetonitrile; and the reaction temperature is -20 to 90°C.

[0037] More specifically, the method for synthesizing resimetidine provided by this invention adopts the following technical solution:

[0038] A method for synthesizing resmetrol, starting with 3-isopropylfuran-2,5-dione compound 1, reacts with hydrazine hydrate to obtain 4-isopropyl-1,2-dihydropyridazine-3,6-dione compound 2, followed by chlorination to obtain 3,6-dichloro-4-isopropylpyridazine compound 3, then hydrolyzes to obtain 6-chloro-4-isopropyldihydropyridazine n-3(4H)-one compound 4, which is then condensed with 4-amino-2,6-dichlorophenol compound 5 to obtain the key intermediate of resmetrol, 6-(4-amino-2,6-dichlorophenyl)-4-isopropylpyridazine-3(2H)-one compound 6. Compound 6 is then nitrosated and condensed with cyanoacetamide compound 7 to obtain intermediate compound 8, and finally cyclized to obtain the target product resmetrol 9.

[0039]

[0040] This invention relates to a method for synthesizing resmetiro, which introduces isopropyl from the starting material 3-isopropylfuran-2,5-dione substrate instead of later derivatization with Grignard reagents to generate isopropyl, thus avoiding unnecessary material loss. The method utilizes intermediate compound 6, which undergoes a diazotization reaction followed by condensation with inexpensive cyanoacetamide for cyclization. The reaction conditions are mild and the conversion rate is high. This route not only significantly shortens the synthetic route and greatly improves route efficiency and reduces process costs, but also reduces the risk of nitrosamines, which is beneficial for improving the purity of the final product and is suitable for scale-up production. Detailed Implementation

[0041] The embodiments of the present invention are described in detail below. These embodiments are implemented based on the technical solution of the present invention, and provide detailed implementation methods and specific operation processes. However, the scope of protection of the present invention is not limited to the following embodiments.

[0042] Example 1

[0043]

[0044] Compound 1 (14.01 g, 100 mmol) was added to a three-necked flask, followed by 70 mL of ethanol, 12.52 g of 80% hydrazine hydrate (200 mmol), and 6.01 g of acetic acid (100 mmol). The mixture was heated to reflux for 6–8 hours. A portion of the ethanol was removed by rotary evaporation, the mixture was cooled, stirred into a slurry, filtered, and dried to obtain compound 2 (14.24 g, 92.4%).

[0045] MS(ESI)m / z = 155.1 [M+H] + .

[0046] 1HNMR (CDCl3, 500MHz) δ7.41 (s, 1H), 3.22-3.32 (m, 1H), 1.32 (d, J = 7.0Hz, 6H).

[0047] In Example 1, the reaction solvent ethanol can be replaced by ethyl acetate, isopropyl acetate, methanol, isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, or acetonitrile; acetic acid can be omitted, or trifluoroacetic acid or p-toluenesulfonic acid can be used instead.

[0048] Example 2

[0049]

[0050] Compound 2 (15.42 g, 100 mmol) was added to a three-necked flask, followed by 154 mL of toluene, 20.24 g of triethylamine (200 mmol), and 38.33 g of phosphorus oxychloride (250 mmol). The mixture was heated to 105–110 °C and reacted for 6–8 hours. The reaction was quenched by slowly adding 77 mL of water, and the mixture was stirred and separated. The toluene layer was washed once with water and concentrated to obtain intermediate 3, an oily substance, which was directly added to the next reaction step.

[0051] In Example 2, triethylamine may be used without alkali, or triethylamine may be replaced by diisopropylethylamine, N,N-dimethylaniline, pyridine, DMAP, or DABCO; phosphine oxychloride may be replaced by thionyl chloride, phosphorus trichloride, or phenyl dichlorophosphate; and the reaction solvent toluene may be replaced by dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, or acetonitrile.

[0052] Example 3

[0053]

[0054] Compound 3 (~100 mmol) obtained in Example 2 was added to 77 mL of acetic acid and heated to reflux for 6-8 hours. Some of the acetic acid was removed by rotary evaporation, water was slowly added, the mixture was cooled, stirred, filtered, and dried to obtain compound 4 (14.71 g, 85.2% of the two-step reaction).

[0055] MS(ESI)m / z = 173.0 [M+H] + .

[0056] 1 HNMR(DMSO-d6,500MHz)δ13.08(s,1H),7.29(s,1H),2.94-3.04(m,1H),1.14(d,J=7.0Hz,6H)

[0057] In Example 3, acetic acid can be replaced by sodium acetate, lithium hydroxide, sodium hydroxide, or potassium hydroxide.

[0058] Example 4

[0059]

[0060] Compound 5 (18.69 g, 105 mmol) and acetonitrile (86.5 mL) were added to a three-necked flask and stirred until dissolved. Then, diisopropylethylamine (38.77 g, 200 mmol) and compound 4 (17.26 g, 100 mmol) were added. The mixture was heated to 45–50 °C and reacted for 10–16 hours. After the reaction was complete, most of the acetonitrile was concentrated and distilled off. Water (173 mL) was added and the mixture was stirred until it reached a paste. The paste was slowly cooled to 0–10 °C, filtered, and dried to obtain compound 6 (28.15 g, 89.6%).

[0061] In Example 4, diisopropylethylamine can be replaced by potassium carbonate, sodium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, LiHMDS, n-butyllithium, triethylamine, N,N-dimethylaniline, pyridine, DMAP, or DABCO; the reaction solvent acetonitrile can be replaced by dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, or toluene.

[0062] Example 5

[0063]

[0064] In a three-necked flask, compound 6 (31.42 g, 100 mmol) and 5% dilute hydrochloric acid (146 g, 200 mmol) were added and stirred until dissolved. The mixture was then cooled to 0–5 °C, and sodium nitrite (6.90 g, 100 mmol) was added. The mixture was reacted at 0–10 °C for 1 hour to prepare a diazo compound solution. In another reaction flask, ethanol (157 mL), cyanoacetamide (140 mmol), and sodium acetate (200 mmol) were added. The mixture was stirred and cooled to 0–5 °C. The prepared diazo compound solution was slowly added dropwise to the mixture. After the addition was complete, the temperature was slowly raised to room temperature and the reaction was carried out for 3–5 hours. After the reaction was completed, most of the ethanol was distilled off. The mixture was slowly cooled to 0–5 °C, filtered, and dried to obtain compound 8 (38.26 g, 93.5%).

[0065] MS(ESI)m / z = 409.1 [M+H] + .

[0066] 1HNMR(DMSO-d6,500MHz)δ12.21(s,1H),11.82(s,1H),8.13(s,1H),7.90(s,2H),7.58(s,1H),7.37(s,1H),2.98-3.09(m,1H),1.19(d,J=6.5Hz,6H)

[0067] In Example 5, hydrochloric acid may be omitted or replaced with sulfuric acid, phosphoric acid, or nitric acid; sodium nitrite may be replaced with isoamyl nitrite or tert-butyl nitrite; sodium acetate may be replaced with potassium acetate or acetic acid; and the reaction solvent ethanol may be replaced with dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, ethyl acetate, isopropyl acetate, methanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, acetonitrile, or water.

[0068] Example 6

[0069]

[0070]

[0071] Compound 8 (40.92 g, 100 mmol) and tetrahydrofuran (204 mL) were added to a three-necked flask and stirred until homogeneous. Triethylamine (20.24 g, 200 mmol) and carbonyl diimidazole (19.46 g, 120 mmol) were then added. The mixture was heated to 48–52 °C and reacted for 8–10 hours. After the reaction was complete, the mixture was concentrated to remove most of the solvent. Dilute hydrochloric acid (2% (246 mL)) was added, and the mixture was slowly cooled to 0–5 °C and stirred until a paste was formed. The paste was filtered, and the crude product was recrystallized from isopropanol and water to obtain resmetiro product 9 (40.26 g, 92.5%, purity ≥99.8%).

[0072] In Example 6, carbonyl diimidazole can be replaced by phosgene, methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, tert-butyl chloroformate, phenyl chloroformate, dimethyl carbonate, diethyl carbonate, tert-butylphenyl carbonate, or Boc anhydride; triethylamine can be omitted, or triethylamine can be replaced by sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, DMAP, pyridine, or DABCO; the reaction solvent tetrahydrofuran can be replaced by dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, ethyl acetate, isopropyl acetate, 2-methyltetrahydrofuran, toluene, or acetonitrile.

Claims

1. A method for synthesizing resmetiro, characterized in that, This includes cyclizing compound 8 with a carbonylating agent to obtain the target product 9; 8 9 The carbonylating agent is selected from carbonyl diimidazole, and triethylamine is added.

2. A method for synthesizing resmetiro, characterized in that, Starting with 3-isopropylfuran-2,5-dione compound 1, it was first reacted with hydrazine hydrate to give 4-isopropyl-1,2-dihydropyridazine-3,6-dione compound 2, which was then chlorinated to give 3,6-dichloro-4-isopropylpyridazine compound 3. Subsequently, it was hydrolyzed to give 6-chloro-4-isopropyldihydropyridazine n-3(4H)-one compound 4, which was then condensed with 4-amino-2,6-dichlorophenol compound 5 to give the key intermediate of resmetiro, 6-(4-amino-2,6-dichlorophenyl)-4-isopropylpyridazine-3(2H)-one compound 6. Compound 6 was nitrosated and then condensed with cyanoacetamide compound 7 to give intermediate compound 8. Compound 8 was cyclized under the action of a carbonylating agent to give the target product resmetiro 9. The carbonylating agent was selected from carbonyl diimidazole, and the cyclization reaction was carried out under the action of triethylamine. 。

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